Sex Differences in Antinociceptive Tolerance Development to Δ9‐THC and CP55,940 in Wild‐type and Desensitization‐Resistant S426A/S430A Mice

Abstract

Tolerance to the antinociceptive effects of cannabinoid agonists limit their therapeutic potential. Male mice expressing a desensitization‐resistant form of the CB1 receptor (S426A/S430A) show delayed tolerance development to the hypothermic and antinociceptive effects of Δ9‐THC, a strongly desensitizing partial CB1 agonist. However, it remains unknown what effect this mutation might have on altering tolerance to the synthetic full CB1 agonist CP55,940 and whether tolerance development to Δ9‐THC and CP55,940 differ in a sex‐specific manner. The purpose of the current study was to investigate whether the S426A/S430A mutation alters antinociceptive and/or hypothermic tolerance to CP55,940 and Δ9‐THC and whether these effects are sex‐specific. Tolerance to Δ9‐THC (30 mg/kg) and CP55,940 (0.3–0.6 mg/kg) was assessed in two ways: following once‐daily injections across 7–10 consecutive days and via shifts in the cumulative dose response curves following 3–7 days of treatment with each agonist in both male and female wild‐type and S426A/S430A mice. Once‐daily drug administration resulted in slower tolerance development to the effects of CP55,940 versus Δ9‐THC in male and female wildtype mice. The S426A/S430A mutation delayed tolerance to the antinociceptive effect of CP55,940 in male mice and delayed tolerance to both the antinociceptive and hypothermic effects of CP55,940 and Δ9‐THC in female mice. In our cumulative dose responses, we found that the S426A/S430A mutation rendered both male and female mice more sensitive to the effects of Δ9‐THC compared to wild‐type mice. Overall, our results demonstrate that sex and agonist specific mechanisms may mediate cannabinoid tolerance. These studies showcase the antinociceptive therapeutic potential of cannabinoid agonists and offer potential avenues to better understand tolerance to their analgesic effects following prolonged exposure.Support or Funding InformationNIH grants DA036385 (DJM), DA037355 (DJM), Pennsylvania Department of Health using CURE Tobacco Settlement Funds (DJM), Penn State University College of Medicine Department of Anesthesiology and Perioperative Medicine Start Up FundsThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.